SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia

• Published in: Leukemia 2020-07, Vol.34 (7), p.1787-1798
• Main Authors: Sinnakannu, Joanna R., Lee, Kian Leong, Cheng, Shanshan, Li, Jia, Yu, Mengge, Tan, Siew Peng, Ong, Clara Chong Hui, Li, Huihua, Than, Hein, Anczuków-Camarda, Olga, Krainer, Adrian R., Roca, Xavier, Rozen, Steven G., Iqbal, Jabed, Yang, Henry, Chuah, Charles, Ong, Sin Tiong
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/109; 13/21; 13/51; 13/89; 38; 38/39; 38/90; 631/67/1990/283/1896; 631/67/395; 82; 82/1; Antimitotic agents; Antineoplastic agents; B cells; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Bone marrow; Bone Marrow - drug effects; Bone Marrow - metabolism; Bone Marrow - pathology; Cancer Research; Care and treatment; CD34 antigen; Chronic myeloid leukemia; Critical Care Medicine; Cytokines; Cytokines - pharmacology; Depletion; Drug Resistance, Neoplasm - drug effects; Gene Expression Regulation, Neoplastic; Gene sequencing; Hematology; Hemopoiesis; Heterogeneity; Humans; Imatinib; Imatinib Mesylate - pharmacology; Inhibitor drugs; Intensive; Internal Medicine; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Medicine; Medicine & Public Health; Myeloid leukemia; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncology; Prognosis; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Resistance factors; Ribonucleic acid; RNA; Sensitivity; Serine-Arginine Splicing Factors - genetics; Serine-Arginine Splicing Factors - metabolism; Splicing factors; Targeted cancer therapy; Tumor Cells, Cultured; Tyrosine
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-020-0732-1

Patients with chronic myeloid leukemia (CML) who are treated with tyrosine kinase inhibitors (TKIs) experience significant heterogeneity regarding depth and speed of responses. Factors intrinsic and extrinsic to CML cells contribute to response heterogeneity and TKI resistance. Among extrinsic factors, cytokine-mediated TKI resistance has been demonstrated in CML progenitors, but the underlying mechanisms remain obscure. Using RNA-sequencing, we identified differentially expressed splicing factors in primary CD34 + chronic phase (CP) CML progenitors and controls. We found SRSF1 expression to be increased as a result of both BCR-ABL1- and cytokine-mediated signaling. SRSF1 overexpression conferred cytokine independence to untransformed hematopoietic cells and impaired imatinib sensitivity in CML cells, while SRSF1 depletion in CD34 + CP CML cells prevented the ability of extrinsic cytokines to decrease imatinib sensitivity. Mechanistically, PRKCH and PLCH1 were upregulated by elevated SRSF1 levels, and contributed to impaired imatinib sensitivity. Importantly, very high SRSF1 levels in the bone marrow of CML patients at presentation correlated with poorer clinical TKI responses. In summary, we find SRSF1 levels to be maintained in CD34 + CP CML progenitors by cytokines despite effective BCR-ABL1 inhibition, and that elevated levels promote impaired imatinib responses. Together, our data support an SRSF1/PRKCH/PLCH1 axis in contributing to cytokine-induced impaired imatinib sensitivity in CML.